Age has a Minimal Effect on the Impact Performance of Field-Used Bicycle Helmets.
Helmet manufacturers recommend replacing a bicycle helmet after an impact or after anywhere from 2 to 10 years of use. The goal of this study was to quantify the effect of helmet age on peak headform acceleration during impact attenuation testing of field-used bicycle helmets. Helmets were acquired by donation from consumers and retail stores, and were included in the study if they were free of impact-related damage, had a legible manufacture date label, and were certified to at least one helmet standard. Helmets (n = 770) spanning 0-26 years old were drop tested to measure peak linear headform acceleration during impacts to the right and left front regions of the helmets at two impact speeds (3.0 and 6.2 m/s). General linear mixed models were used to assess the effect of age and three covariates (helmet style, size and certification impact speed) on peak acceleration. Overall, age was related to either no difference or a statistically significant but small increase (≤0.76 g/year of helmet age) in peak headform acceleration. Extrapolated across 20 years, age-related differences were less than both style- (traditional vs. BMX) and size-related differences. The age-related differences were also less than the variability observed between different helmets after accounting for style, size and certification effects. These findings mean that bicycle helmets (up to 26-year-old traditional helmets and 13-year-old BMX helmets) do not lose their ability to attenuate impacts with age; however, other helmet features that may change with age were not evaluated in this study.


Expression of cyclooxygenase-2 in human transitional cell carcinoma of the urinary bladder.
Recent studies suggest that expression of cyclooxygenase-2 (Cox-2) is elevated in transitional cell carcinoma (TCC) of the urinary bladder and that inhibition of Cox-2 activity suppresses bladder cancer in experimental animal models. We have investigated the expression of Cox-2 protein in human TCCs (n = 85), in in situ carcinomas (Tis) of the urinary bladder (n = 17), and in nonneoplastic urinary bladder samples (n = 16) using immunohistochemistry. Cox-2 immunoreactivity was detected in 66% (67 of 102) of the carcinomas, whereas only 25% (4 of 16) of the nonneoplastic samples were positive (P: < 0.005). Cox-2 immunoreactivity localized to neoplastic cells in the carcinoma samples. The rate of positivity was the same in invasive (T1-3; 70%, n = 40) and in noninvasive (Tis and Ta; 65%, n = 62) carcinomas, but noninvasive tumors had a higher frequency (32%) of homogenous pattern of staining (>90% of the tumor cells positive) than the invasive carcinomas (10%) (P: < 0.05). However, several invasive TCCs exhibited the strongest intensity of Cox-2 staining in the invading cells, whereas other parts of the tumor were virtually negative. Finally, strong Cox-2 positivity was also found in nonneoplastic ulcerations (2 of 2) and in inflammatory pseudotumors (2 of 2), in which the immunoreactivity localized to the nonepithelial cells. Taken together, our data suggest that Cox-2 is highly expressed in noninvasive bladder carcinomas, whereas the highest expression of invasive tumors associated with the invading cells, and that Cox-2 may also have a pathophysiological role in nonneoplastic conditions of the urinary bladder, such as ulcerations and inflammatory pseudotumors.


Cognitive Training and Remediation in First-Episode Psychosis: A Literature Review.
BACKGROUND: Neurocognitive and social cognitive impairments are core characteristics of psychotic disorders, which are present in the first episode of psychosis (FEP) and strongly predict poor social functioning. Addressing cognitive impairments through cognitive training and remediation (CTR) may be a crucial component of recovery-oriented treatment. AIMS: The objectives of this review were to (1) evaluate the CTR theoretical basis and intervention components and (2) examine the effects of CTR on cognition and social functioning in FEP. METHOD: A combined search of Ovid Medline, Embase, and Psych Info databases was conducted using keywords. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Quality and risk of bias were assessed using established instruments. RESULTS: Ten randomized controlled trials were included in this review and had an overall fair to poor quality. CTR interventions in FEP utilize a range of theoretical backgrounds, with most including a focus on higher order cognitive processes. Varied doses and intervention components are used. All but one study found improvements in at least one cognitive domain. Global cognition, verbal learning, and memory and executive function were most commonly improved. Three studies found an effect on a range of functional outcomes. CONCLUSIONS: A broad range of CTR interventions have promising effects for addressing cognitive impairments in FEP. Evidence of functional impact is less consistent. Further research is needed in FEP on CTR targeting sensory and perceptual processes, and to identify CTR intervention targets and treatment components that will lead to robust improvements in cognition and functioning.


Practice management. Behind the lines.
The introduction of nurse telephone triage for patients requesting same-day attention in a GP practice has reduced the number of appointments and home visits for these patients. Patients welcome the opportunity to speak to a health professional when they telephone. The practice has found the scheme a useful method of demand management and hopes to expand it.


Flares of Disease in Children with Clinically Inactive Juvenile Idiopathic Arthritis Were Not Correlated with Ultrasound Findings.
The validity of our current definitions for clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA) based on physical examination is challenged by the development of advanced musculoskeletal imaging tools. We aimed to prospectively determine the prevalence of abnormal ultrasound (US) findings in children with CID in JIA and their clinical significance. Children aged ≥ 4 years with CID and a history of arthritis from a single tertiary center were approached over 1 year. Standard US of knees, tibiotalar joints, subtalar joints, and wrists were performed at baseline and at a followup visit. US images were scored by 2 pediatric musculoskeletal radiologists. Forty children with CID were enrolled and followed clinically. The median duration of inactive disease was 1 year. The most common International League of Associations for Rheumatology JIA categories were extended oligoarticular JIA (30%) and rheumatoid factor-negative polyarthritis (38%). At baseline, among a total of 289 joints scanned, 24 joints (8%) had at least 1 abnormal finding in 18 (45%) of 40 subjects. When evaluated at the individual joint level against flares identified during followup exams, these baseline US findings had a sensitivity of 15% and a positive predictive value of 12%. The predictive performance of the second US was even less. Our study demonstrates that nearly half of children with CID had abnormal US findings in 1 of 8 commonly affected joints. These findings did not correlate with subsequent clinical flares in up to 2 years of followup.


Stimulation of the muscarinic receptor M4 regulates neural precursor cell proliferation and promotes adult hippocampal neurogenesis.
Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis; however, the mechanisms by which acetylcholine mediates neurogenic effects are not completely understood. Here, we report the expression of muscarinic acetylcholine receptor subtype M4 (M4 mAChR) on a subpopulation of neural precursor cells (NPCs) in the adult mouse hippocampus and demonstrate that its pharmacological stimulation promotes their proliferation, thereby enhancing the production of new neurons in vivo. Using a targeted ablation approach, we also show that medial septum (MS) and the diagonal band of Broca (DBB) cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. Although the systemic administration of an M4-selective allosteric potentiator fails to fully rescue the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis, it further exacerbates the impairment in the morphological maturation of adult-born neurons. Collectively, these findings reveal stage-specific roles of M4 mAChRs in regulating adult hippocampal neurogenesis, uncoupling their positive role in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic dysfunction.


Triptolide Attenuates Muscular Inflammation and Oxidative Stress in a Delayed-Onset Muscle Soreness Animal Model.
Delayed-onset muscle soreness (DOMS) is associated with exercise-induced muscle damage and inflammation, which is mainly caused by prolonged eccentric exercise in humans. Triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, has been used for treating autoimmune and inflammatory diseases in clinical practice. However, whether triptolide attenuates acute muscle damage is still unclear. Here, we examined the effect of triptolide on carrageenan-induced DOMS in rats. Rats were injected with 3% of carrageenan into their muscles to induce acute left gastrocnemius muscular damage, and triptolide treatment attenuated carrageenan-induced acute muscular damage without affecting hepatic function. Triptolide can significantly decrease lipid hydroperoxide and nitric oxide (NO) levels, proinflammatory cytokine production, and the activation of nuclear factor (NF)-ĸB, as well as increase a reduced form of glutathione levels in carrageenan-treated rat muscles. At the enzyme levels, triptolide reduced the inducible nitric oxide synthase (iNOS) expression and muscular myeloperoxidase (MPO) activity in carrageenan-treated DOMS rats. In conclusion, we show that triptolide can attenuate muscular damage by inhibiting muscular oxidative stress and inflammation in a carrageenan-induced rat DOMS model.


Automatic prostate segmentation based on fusion between deep network and variational methods.
Segmentation of prostate from magnetic resonance images (MRI) is a critical process for guiding prostate puncture and biopsy. Currently, the best results are obtained by Convolutional Neural Network (CNN). However, challenges still exist when applying CNN to segment prostate, such as data distribution issue caused by insubstantial and inconsistent intensity levels and vague boundaries in MRI. To segment prostate gland from a MRI dataset including different prostate images with limited resolution and quality. We propose and apply a global histogram matching approach to make intensity distribution of the MRI dataset closer to uniformity. To capture the real boundaries and improve segmentation accuracy, we employ a module of variational models to help improve performance. Using seven evaluation metrics to quantify improvements of our proposed fusion approach compared with the state of art V-net model resulted in increase in the Dice Coefficient (11.2%), Jaccard Coefficient (13.7%), Volumetric Similarity (12.3%), Adjusted Rand Index (11.1%), Area under ROC Curve (11.6%), and reduction of the Mean Hausdorff Distance (16.1%) and Mahalanobis Distance (2.8%). The 3D reconstruction also validates the advantages of our proposed framework, especially in terms of smoothness, uniformity, and accuracy. In addition, observations from the selected examples of 2D visualization show that our segmentation results are closer to the real boundaries of the prostate, and better represent the prostate shapes. Our proposed approach achieves significant performance improvements compared with the existing methods based on the original CNN or pure variational models.


Cystic kidney diseases and planar cell polarity signaling.
Renal cystic diseases are a major clinical concern as they are the most common genetic cause of end-stage renal disease. While many of the genes causing cystic disease have been identified in recent years, knowing the molecular nature of the mutations has not clarified the mechanisms underlying cyst formation. Recent research in model organisms has suggested that cyst formation may be because of defective planar cell polarity (PCP) and/or ciliary defects. In this review, we first outline the clinical features of renal cystic diseases and then discuss current research linking our understanding of cystic kidney disease to PCP and cilia.


An interactive psychoeducational intervention for women at risk of developing an eating disorder.
This study evaluated a synchronous Internet-delivered intervention (chat room) for improving eating habits and body image in college-age women at risk for developing an eating disorder. Sixty at-risk women (mean age = 18.9, SD = 2.4; 65.0% Caucasian, 19% Latino/Hispanic, 8% Asian/Pacific Islander, 3% African American, 5% other; mean body mass index = 25.6, SD = 5.7) were randomly assigned to intervention (n = 30) or control (n = 30) groups. Once a week for 8 weeks, participants used a private chat room for a 1-hr moderated discussion focused on improving body image and eating behaviors. Additional treatment components included psychoeducation, asynchronous support, homework, and summaries. Assessments were conducted at baseline, posttreatment, and 10 weeks after posttreatment. Participants indicated high satisfaction with the intervention mode. Intervention participants significantly reduced eating pathology and improved self-esteem over controls at follow-up. These findings suggest that synchronous, Internet-delivered programs are efficacious and have potential to reduce problematic attitudes and behaviors that may lead to eating disorders among college-age women.


Screening for celiac disease in asymptomatic children with Down syndrome: cost-effectiveness of preventing lymphoma.
Studies demonstrate an increased prevalence of celiac disease in persons with Down syndrome, leading some organizations and authors to recommend universal screening of children with Down syndrome. However, many children with Down syndrome are asymptomatic, and the long-term implications of screening are unknown. The complication of celiac disease that leads to mortality in the general population is non-Hodgkin's lymphomas. The purpose of this research in asymptomatic children with Down syndrome was to (1) calculate the number needed to screen to prevent a single case of lymphoma and (2) present a cost-effectiveness study of screening. We constructed a decision tree using probabilities derived from the published literature for Down syndrome or from the general population where Down syndrome-specific data were not available. Celiac disease was determined by serologic screening and confirmation with intestinal biopsy. Sensitivity analysis was used to alter probability estimates affecting the cost of preventing lymphoma. Using our baseline values, the no-screen strategy is dominant; that is, screening not only costs more but also results in fewer quality-adjusted life-years. A screening strategy costs more than $500,000 per life-year gained. Screening all asymptomatic children with Down syndrome for celiac disease costs almost $5 million to prevent a single case of lymphoma. These analyses do not support the cost-effectiveness of screening, and more data are needed before recommendations to screen asymptomatic children with Down syndrome for celiac disease can be made.


Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice.
To investigate the role of membrane-type matrix metalloproteinase-1 (MT1-MMP) in mammary gland development and tumorigenesis, transgenic mice overexpressing MT1-MMP in mammary gland under the control of the mouse mammary tumor virus long terminal repeat-promoter were generated. The mouse mammary tumor virus/MT1-MMP transgenic mice displayed abnormalities in 82% of female mammary glands. The abnormalities were verified as lymphocytic infiltration, fibrosis, hyperplasia, alveolar structure disruption, dysplasia, and adenocarcinoma. Northern and reverse transcription-PCR analyses demonstrated that MT1-MMP mRNA was overexpressed in mammary glands exhibiting abnormalities. Western blot analysis and immunohistochemical studies have revealed that the protein expression level was also increased in these glands. In addition, the beta-casein gene as a functional epithelial cell marker was poorly expressed in the mammary glands of transgenic mice exhibiting abnormalities. Gelatin zymography showed significantly increased MMP-2 activation in these mammary glands. These results showed that overexpression of MT1-MMP induced remodeling of the extracellular matrix and tumor formation in the mammary glands of transgenic mice. Therefore, we suggest that overexpression of MT1-MMP may play a key role in development and tumorigenesis in mammary glands.


Effects of aminaftone 75 mg TID on soluble adhesion molecules: a 12-week, randomized, open-label pilot study in patients with systemic sclerosis.
Vasculopathy is one of the hallmarks of systemic sclerosis (SSc), characterized by endothelial activation and over expression of adhesion molecules. A preliminary in vitro study has suggested that aminaftone, a naphtohydrochinone used in the treatment of capillary disorders, may downregulate the expression of adhesion molecules in endothelial cells. This study investigated the ex vivo effects of aminaftone on soluble adhesion molecule concentrations in patients with SSc. This randomized, open-label pilot study was conducted in patients with SSc. Patients received baseline treatment for Raynaud's phenomenon (eg, calcium channel blockers and IV cyclic iloprost) with (test) or without (control) aminaftone 75 mg or placebo TID for 12 weeks. Standard treatment for Raynaud's phenomenon was allowed as long as the dose was stable for >or=3 months prior to randomization. Concentrations of soluble E-selectin adhesion molecule 1 (sELAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble intracellular adhesion molecule 1 (sICAM-1) were measured at baseline and 12 weeks, and their variation was tested using the analysis of variance for repeated measures with statistical correction. Laboratory analyses were performed by experienced personnel blinded to treatment assignment. A total of 24 patients were enrolled (21 women, 3 men; mean age, 53.4 years; aminaftone, 12 patients; control, 12 patients). Decreases in mean (SD) sELAM-1 and sVCAM-1 concentrations were significantly greater in treated patients (sELAM-1, from 17.0 [7.8] to 11.9 [9.0] pg/mL; sVCAM-1, from 51.2 [12.9] to 40.8 [13.8] ng/mL) compared with controls (sELAM-1, from 20.3 [9.9] to 20.4 [10.5] pg/mL; sVCAM-1, from 56.8 [49.6] to 62.7 [40.6] ng/mL) (both, P < 0.05 [analysis of variance or repeated measures after Bonferroni correction]). No significant changes in sICAM-1 concentrations versus controls were observed. In this small pilot study in this select group of patients with SSc, aminaftone was associated with downregulation of sELAM-1 and sVCAM-1 concentrations. Studies evaluating the potential role of aminaftone in the treatment of vascular sclerodermal disease and SSc are warranted.


Erosion vs. recovery of coral reefs after 1998 El Niño: Chagos reefs, Indian Ocean.
Three years after most corals died on the central Indian Ocean reefs of Chagos, erosion and recovery were studied to 30 m depth. Mortality was near-total to 15 m deep in northern atolls, and to > 35 m in central and southern atolls. Some reef surfaces have 'dropped' 1.5 m due to the loss of dense coral thickets. Coral bioerosion is substantial, reducing 3-D reef 'structure' and forming unconsolidated rubble. Juvenile corals are abundant, though mostly on eroding or unstable substrates, and are of less robust species. Reef fish abundance and diversity at 15 m depth remains high; species dependent on corals have diminished, while some herbivores and detritivores have increased. A new sea surface temperature (SST) data set shows that mean SST has risen 0.65 degree C since 1950. The critical SST causing the mortality in Chagos was 29.9 degrees C.


Vitamin E and carotene status in pre-eclamptic pregnant women from India.
The imbalance between oxidative stress and the protective antioxidant system of the body enhanced the free radical mediated membrane lipid peroxidation and possibly the vascular endothelial damage due to peroxidation plays a major role in the aetiology of pre-eclampsia. With present day awareness on micronutrient antioxidants, we did investigate vitamin E and carotene status in Indian pre-eclamptic pregnant and full term normotensive pregnant women. Fresh vegetables and oils are considered to be good sources of vitamin E and carotene. The subjects were used to have good intake of fresh vegetable and oil as per Indian standard prescribed by Indian council of Medical research (ICMR) for this sub-continent. The blood samples were processed for RBC vitamin E, serum carotene and serum cholesterol analysis. Routine laboratory tests like hemogram, serum urea, urate, malonyldialdehyde, urine sugar and albumin were performed. All pregnant subjects, both cases and control were maternal and gestational age matched. Routine check up showed no significant differences in means of white blood cell count, Hb/hematocrit and platelets. Serum urate and malonyldialdehyde were significantly raised in pre-eclamptic cases. The severely affected pre-eclamptic cases (diastolic BP >100 mmHg with proteinuria 2+ and more) showed markedly low levels of vitamin E and carotene whereas their levels were comparable between mild cases (diastolic BP <100 mmHg with+/-trace albuminuria) and normotensive pregnant control. The study concluded that the levels of vitamin E and carotene were markedly lowered in severe pre-eclamptic pregnant women from India. The mild pre-eclamptic cases did not show noticeable changes from that of control pregnant women. Further studies are needed to verify their therapeutic and prophylatic roles against pre-eclamptic complication suring pregnancy.


Protein kinase activity of the insulin receptor.
The insulin receptor is an integral membrane glycoprotein (Mr approximately 300,000) composed of two alpha-subunits (Mr approximately 130,000) and two beta-subunits (Mr approximately 95,000) linked by disulphide bonds. This oligomeric structure divides the receptor into two functional domains such that alpha-subunits bind insulin and beta-subunits possess tyrosine kinase activity. The amino acid sequence deduced from cDNA of the single polypeptide chain precursor of human placental insulin receptor revealed that alpha- and beta-subunits consist of 735 and 620 residues, respectively. The alpha-subunit is hydrophilic, disulphide-bonded, glycosylated and probably extracellular. The beta-subunit consists of a short extracellular region which links the alpha-subunit through disulphide bridges, a hydrophobic transmembrane region and a longer cytoplasmic region which is structurally homologous with other tyrosine kinases like the src oncogene product and EGF receptor kinases. The cellular function of insulin receptors is dual: transmembrane signalling and endocytosis of hormone. The binding of insulin to its receptor on the cell membrane induces transfer of signal from extracellular to cytoplasmic receptor domains leading to activation of cell metabolism and growth. In addition, hormone-receptor complexes are internalized leading to intracellular proteolysis of insulin, whereas receptors are recycled to the membrane. These phenomena are kinetically well-characterized, but their molecular mechanisms remain obscure. Insulin receptor in different tissues and animal species are homologous in their structure and function, but show also significant differences regarding size of alpha-subunits, binding kinetics, insulin specificity and receptor-mediated degradation. We suggest that this heterogeneity of receptors may be linked to the diversity in insulin effects on metabolism and growth in various cell types. The purified insulin receptor phosphorylates its own beta-subunit and exogenous protein and peptide substrates on tyrosine residues, a reaction which is insulin-sensitive, Mn2+-dependent and specific for ATP. Tyrosine phosphorylation of the beta-subunit activates receptor kinase activity, and dephosphorylation with alkaline phosphatase deactivates the kinase. In intact cells or impure receptor preparations, a serine kinase is also activated by insulin. The cellular role of two kinase activities associated with the insulin receptor is not known, but we propose that the tyrosine- and serine-specific kinases mediate insulin actions on metabolism and growth either through dual-signalling or sequential pathways.(ABSTRACT TRUNCATED AT 400 WORDS)


Iliocaval Reconstruction: Review of Technique, Challenges, and Outcomes.
Iliocaval thrombosis is a major source of morbidity for patients, with a range of clinical presentations, including recurrent lower extremity deep venous thrombosis and postthrombotic syndrome. Endovascular reconstruction of chronic iliocaval occlusion has been demonstrated to be a technically feasible procedure that provides long-lasting symptom relief in combination with antithrombotic therapy and close clinical monitoring. Herein, we describe the etiologies of iliocaval thrombosis, patient assessment, patient management prior to and after intervention, procedural techniques, and patient outcomes.


[Utility of 201Tl washout in syndrome X patients].
The term Syndrome X defines a group of patients who present symptoms of typical angina pectoris, positive exercise test and normal coronaries in the arteriogram. This study aims to compare the results of 201Tl scan images and washout in Syndrome X patients. 24 patients with typical angina and normal arteriogram and 30 normal controls were studied with 201Tl SPECT to evaluate uptake and washout. 201Tl perfusion defects were found in 3 out of 24 (12.5%) and washout defects in 22 out of 24 (91.6 %). There is a statistically significant reduction (0 < 0.05) in thallium uptake and washout in patients with syndrome X compared to the control group. In addition, patients with syndrome X had a higher thallium uptake at rest than during exercise compared to the healthy subjects. Analysis of the 201Tl washout and thallium uptake can provide addition information in the evaluation of patients with syndrome X since the visual assessment of the cardiac scintigraphy with 201Tl is of limited value. Alterations of the myocardial perfusion in patients with chest pain and normal coronaries can be detected non-invasively with a complete scintigraphic study.


Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration.
In order to better define variables and factors that may influence the pain response to radiation, and to look for a radiation regimen that can assure the highest percentage and the longest duration of pain relief, we performed a prospective, although not randomized, study on patients with bone metastases from various primary sites. From December 1988 to March 1994, 205 patients with a total of 255 solitary or multiple bone metastases from several primary tumors were treated in our radiotherapy center with palliative intent. Irradiation fields were treated with three main fractionation schedules: (1) Conventional fractionation: 40-46 Gy/20-23 fractions in 5-5.5 weeks; (2) Short course: 30-36 Gy/10-12 fractions in 2-2.3 weeks; (3) Fast course: 8-28 Gy/1-4 consecutive fractions. Pain intensity was self-assessed by patients using a visual analogic scale graduated from 0 (no pain) to 10 (the strongest pain one can experience). Analgesic requirement was assessed by using a five-point scale, scoring both analgesic strength and frequency (0 = no drug or occasional nonopioids; 1 = Nonopioids once daily; 2 = Nonopioids more than once daily; 3 = Mild opioids (oral codeine, pentazocine, etc.), once daily; 4 = Mild opioids more than once daily; 5 = Strong opioids (morphine, meperidine, etc.). Complete pain relief meant the achievement of a score < or = 2 in the pain scale or 0 in the analgesic requirement scale. Partial pain relief indicated a score of 3 to 4 or of 1 to 2 on the former and latter scale, respectively. Total pain relief (complete + partial) was observed in 195 (76%) sites, in 158 of which (62%) a complete response was obtained. Metastases from NSC lung tumors appeared to be the least responsive among all primary tumors, with 46% complete pain relief in comparison to 65% and 83% complete relief in breast (p = 0.04) and in prostate metastases (p = 0.002), respectively. A significant difference in pain relief was detected among the several ranges of total dose delivered to the painful metastases, with 81%, 65%, and 46% complete relief rates in the 40-46 Gy, 30-36 Gy (p = 0.03), and 8-28 Gy (p = 0.0001) dose ranges respectively. A straight correlation between total dose and complete pain relief was confirmed by the curve calculated by the logistic model which shows that doses of 30 Gy or more are necessary to achieve complete pain relief in 70% or more of bone metastases. This correlation holds also for the duration of pain control, as shown by the actuarial analysis of time to pain progression. Multivariate analyses, with complete pain relief and time to pain progression as endpoints show a highly significant effect of radiation dose (p = 0.0007) and performance status (p = 0.003), with lower rates of complete pain relief and shorter time to pain progression observed after smaller radiation total doses or higher Eastern Cooperative Oncology Group (ECOG) scores. Although single-dose or short course irradiation is an attractive treatment in reducing the number of multiple visits to radiotherapy departments for patients with painful bone metastases, it is nevertheless clear that aggressive protracted treatments seem to offer significant advantages especially for patients in whom the expected life span is not short.


Vacuolar H(+)-ATPase is not restricted to clear cells of the epididymal epithelium in cattle.
Communication among epididymal epithelial cells creates the best luminal condition where spermatozoa mature, transport and are stored. Vacuolar ATPase (V-ATPase) and cytokeratin 5 (KRT5) have been used as signal indicators for clear and basal cells of the epididymal epithelium, respectively, in mice, rats, bats, and pigs; however, these two markers have not yet been described in the epididymis of bulls. Here, we examined the presence and distribution of the B1 subunit of V-ATPase (B1-VATPase) and KRT5 in the distinct regions of adult bovine epididymides, specifically, the caput, corpus, and cauda. Immunofluorescence staining and confocal microscopy showed that narrow shaped-clear cells were placed in the caput and corpus regions of the bovine epididymis; however, they were absent in the cauda epididymis. In addition, B1-VATPase was highly expressed in the cauda spermatozoa; however, it was rarely detected in the caput spermatozoa. On the other hand, KRT5-positive cells, basal cells, were maintained beneath the basal lamina and they had the traditional form with a dome-shaped morphology from the caput to cauda region of the bovine epididymis. The co-expression of B1-VATPase and KRT5 was confined to basal cells placed in the basal region of the epithelium. In summary, 1) clear cells were present with region-specific localization, 2) B1-VATPase was present in the corpus and cauda spermatozoa but absent in the caput, 3) co-expressed cells with B1-VATPase and KRT5 were present in the adult bovine epididymis, and 4) B1-VATPase was not a specific marker for clear cells in the bovine epididymis. Therefore, the perfect epididymal luminal condition created by the specific expression and localization patterns of B1-VATPase might be necessary to obtain fertilizing capacity of spermatozoa in the bovine epididymis.


The embryonic linker histone dBigH1 alters the functional state of active chromatin.
Linker histones H1 are principal chromatin components, whose contribution to the epigenetic regulation of chromatin structure and function is not fully understood. In metazoa, specific linker histones are expressed in the germline, with female-specific H1s being normally retained in the early-embryo. Embryonic H1s are present while the zygotic genome is transcriptionally silent and they are replaced by somatic variants upon activation, suggesting a contribution to transcriptional silencing. Here we directly address this question by ectopically expressing dBigH1 in Drosophila S2 cells, which lack dBigH1. We show that dBigH1 binds across chromatin, replaces somatic dH1 and reduces nucleosome repeat length (NRL). Concomitantly, dBigH1 expression down-regulates gene expression by impairing RNApol II binding and histone acetylation. These effects depend on the acidic N-terminal ED-domain of dBigH1 since a truncated form lacking this domain binds across chromatin and replaces dH1 like full-length dBigH1, but it does not affect NRL either transcription. In vitro reconstitution experiments using Drosophila preblastodermic embryo extracts corroborate these results. Altogether these results suggest that the negatively charged N-terminal tail of dBigH1 alters the functional state of active chromatin compromising transcription.


1,2,3-Triazolyl esterization of PAK1-blocking propolis ingredients, artepillin C (ARC) and caffeic acid (CA), for boosting their anti-cancer/anti-PAK1 activities along with cell-permeability.
Artepillin C (ARC) and caffeic acid (CA) are among the major anti-cancer ingredients of propolis, and block the oncogenic/melanogenic/ageing kinase PAK1. However, mainly due to their COOH moiety, cell-permeability of these herbal compounds is rather limited. Thus, in this study, in an attempt to increase their cell-permeability without any significant loss of their water-solubility, we have esterized both ARC and CA with the water-soluble 1,2,3-triazolyl alcohol through Click Chemistry. We found that this esterization boosts the anti-cancer activity of ARC and CA by 100 and over 400 folds, respectively, against the PAK-dependent growth of A549 lung cells, but show no effect on the PAK1-independent growth of B16F10 melanoma cells. Confirming this "selective" toxicity, these esters are still capable of blocking the kinase PAK1 strongly in cell culture (with IC50 around 5 µM), and the anti-PAK1 activity of 15A (ARC ester) and 15C (CA ester) appears to be 30-fold and 140-fold higher than ARC and CA, respectively. The 15A and 15C are 8-fold and 70-fold more cell-permeable (through the multi-drug resistant cell line EMT6) than ARC and CA, respectively. These data altogether suggest that both 15A and 15C would be far more useful than propolis for the treatment of a wide variety of PAK1-dependent diseases/disorders such as cancers, Alzheimer's diseases (AD), hypertension, diabetes (type 2), and hyper-pigmentation.


The gonadotrophin-releasing hormone receptor: signalling, cycling and desensitisation.
Sustained stimulation of G-protein coupled receptors (GPCRs) typically causes receptor desensitisation that is mediated by phosphorylation, often within the C-terminal tail of the receptor. The consequent binding of beta-arrestin not only prevents the receptor from activating its G-protein (causing desensitisation) but can also target it for internalisation via clathrin-coated vesicles and can mediate signalling to proteins regulating endocytosis and mitogen-activated protein kinase (MAPK) cascades. GnRH acts via phospholipase C coupled GPCRs on pituitary gonadotrophs. The type I GnRH-receptors (GnRH-Rs) found only in mammals, are unique in that they lack C-terminal tails and apparently do not undergo agonist-induced phosphorylation or bind beta-arrestin. They are therefore resistant to receptor desensitisation and internalise slowly. In contrast, the type II GnRH-Rs, found in numerous vertebrates, possess such tails and show rapid desensitisation and internalisation with concomitant receptor phosphorylation (within the C-terminal tails) and/or binding of beta-arrestin. The binding to beta-arrestin may also be important for association with dynamin, a GTPase that controls cleavage of endosomes from the plasma membrane. Using recombinant adenovirus to express GnRH-R, we have found that blockade of dynamin-dependent endocytosis inhibits internalisation of type II (Xenopus) GnRH-Rs but not type I (human) GnRH-Rs, revealing the existence of functionally distinct routes through which these receptors are internalised. Although type I GnRH-R do not rapidly desensitise, sustained activation of GnRH receptors does cause desensitisation of gonadotrophin secretion, an effect which must therefore involve adaptive responses distal to the receptor. One such response is the GnRH-induced down regulation of inositol 1, 4, 5 trisphosphate receptors that apparently underlies desensitisation of Ca2+ mobilisation in a gonadotroph-derived cell line. Although activation of other GPCRs can down-regulate inositol 1, 4, 5 trisphosphate receptors, the effect of GnRH is atypically rapid and pronounced, presumably because of the receptor's atypical resistance to desensitisation. GnRH-Rs are also expressed in several extra-pituitary sites and these may mediate direct inhibition of proliferation of hormone-dependent cancer cells. Infection with type I GnRH-R expressing adenovirus facilitated expression of high affinity, PLC-coupled GnRH-R in mammary and prostate cancer cells and these mediated pronounced antiproliferative effects of receptor agonists. No such effect was seen in cells transfected with a type II GnRH-R, implying that it is mediated most efficiently by a non-desensitising receptor. Thus it appears that the GnRH-Rs have undergone a period of rapidly accelerated molecular evolution that is of functional relevance to GnRH-R signalling in pituitary and extra-pituitary sites.


Nitrogen metabolism and route of excretion in beef feedlot cattle fed barley-based backgrounding diets varying in protein concentration and rumen degradability.
The objectives of the study were to characterize the effects of CP concentration and ruminal degradability of barley-based backgrounding diets on route and chemical form of N excretion, ruminal fermentation, microbial protein synthesis, and nutrient digestion in beef cattle. Four Angus heifers (479 ± 14.6 kg average BW) with ruminal and duodenal cannulas were used in an experiment designed as a 4 × 4 Latin square. The basal diet consisted of 54% barley silage and 46% barley grain-based concentrate (DM basis). Dietary treatments included the basal diet with no added protein (12% CP) or diets formulated to contain 14% CP by supplementation with urea (UREA), urea and canola meal (UREA+CM), or urea, corn gluten meal, and xylose-treated soybean meal (UREA+CGM+xSBM). The amount of feed offered was restricted to 95% of ad libitum intake. There was no effect of the diets on DMI (P = 0.38), and therefore, N intake was less (P < 0.05) in heifers fed the 12% CP diets than the 14% CP diets. Fecal N output was not affected by the diet (P = 0.15), but urine N (P < 0.10) and urea N output were greater (P < 0.05) in heifers fed the 14% CP than the 12% CP diets. There was no effect of CP degradability (P > 0.10) on the amount of urine N output. Urine N output was 38.9 and 45.1 ± 5.50% of N intake in heifers fed the 12% CP and 14% CP diets (P < 0.05), respectively. Urea N, the form of N most susceptible to NH3-N volatilization and loss, was the major form of N in urine (75.5% in heifers fed the 12% CP diet and 81.4 ± 1.7% in heifers fed the 14% CP diets; P < 0.05). Supplemental RDP (UREA+CM) and RUP combined with urea (UREA+CGM+xSBM) to provide 14% CP increased (P < 0.05) ruminal NH3-N but had no effect on ruminal peptide N (P = 0.62) and free AA N (P = 0.18) concentration, the flow of microbial (P = 0.34) and feed (P = 0.55) N, and ruminal (starch, P = 0.11; NDF, P = 0.78) and total tract nutrient digestibility (OM, P = 0.21; starch, P = 0.16). Supplementation of barley-based backgrounding diets containing 12% CP with NPN alone or combined with ruminally degradable and undegradable true protein to attain 14% CP had no effect on fecal N output, but urine N and urea N increased irrespective of protein source. In addition, the ruminal degradability of the protein sources did not influence the composition of protein flowing to the intestine and site and extent of nutrient digestibility.


CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines.
The highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2B(intron5) and CHMP2B(Delta10) in cultured hippocampal neurons modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2B(Delta10) induced a drop in frequency and amplitude of spontaneous excitatory postsynaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development.


A murine locus on chromosome 18 controls NKT cell homeostasis and Th cell differentiation.
Th cell differentiation is a critical event in the adaptive immune response. C57BL strains develop predominant Th1 responses while BALB/c develops a predominant Th2 response. To identify quantitative trait loci controlling this variation, we performed Th1/Th2 differentiation assays of F(1) x BALB/c progeny. A single strong quantitative trait locus was identified on chromosome 18, with weaker effects detectable on chromosomes 5, 12, and 14. By preparing a congenic BALB.B10.D2c18 strain, we were able to demonstrate that this single locus was sufficient to "repolarize" spleen cell cultures. This difference was not due to intrinsic differences in CD4(+) T cells. Rather, introgression of the chromosome 18 locus into BALB/c disrupted Va14Ja18 NKT cell homeostasis resulting in the almost complete absence of this T cell subset. Taken together, these data indicate that genes within chromosome 18 control strain-dependent development of Va14Ja18 NKT cells.


A WEB-based telePACS using an asymmetric satellite system.
We have developed a WWW-based TelePACS that can access every permitted PACS server via the Internet. Java programming techniques were used to implement the system, which can access and retrieve medical information and images through Web browsers only such as Netscape without specific tools. We also have developed a consolidator that performs as a manager to connect a conventional PACS server to a Web-based TelePACS server. We have developed the Asymmetric Satellite Data Communication System (ASDCS) as a fast communication system. The ASDCS uses a receive-only satellite link for data delivery and a terrestrial network for control communication. In conclusion, we were able to develop a cost-effective and fast PACS using Web technology. Web technology expanded the scope of use for a dedicated PACS from intrahospital to public use.


Total intracorporeal robotic cystectomy: are we there yet?
To provide discussion on several recently published case series describing complete intracorporeal robotic cystectomy. Are we making a complex and expensive procedure more challenging or are there patient benefits to be realized from a complete minimally invasive approach? We discuss how effective and cost-efficient a complete intracorporeal approach is, review the updates and comment on the future direction of robot-assisted radical cystectomy (RARC). Several centers have recently reported a series of RARC with intracorporeal urinary diversion. Baseline demographics, complication rates and oncological outcome data were comparable to previously published open radical cystectomy series, as well as robotic cystectomy with extracorporeal urinary diversion series. In centers experienced in robotics, comparable outcomes were achieved early in the series with no significant difference in lymph node yields, positive surgical margin rates or complication rates. However, operation times and patient's length of stay (LOS) continued to improve, suggesting that aspect of the learning curve is longer than previously thought. Benefits such as decreased blood loss and reduced LOS, commonly associated with minimally invasive surgery, were seen and while costs of RARC remain prohibitive, reducing operative times and LOS will improve cost analysis. RARC with totally intracorporeal urinary diversion is technically feasible with good early and intermediate-term oncological and complication rate results. High-volume centers with expertise can deliver a complete intracorporeal robotic cystectomy with no increase in the complication rates or additional costs compared to RARC with extracorporeal urinary diversion. Further long-term oncological and functional data and the results of prospective randomized controlled trials are both pending to confirm these findings.


Analysis method for psychological and physiological responses to body massage "Using POMS and HRV".
This study aimed to compare and proposed an analytical method for evaluating the effectiveness of massage using various measurement parameters. The parameters were divided psychologically using the Profile of Mood States (POMS) and physiologically using heart rate variability. In the experiment, the psycho-physiological effects of the rest(a) and two massage techniques (b, c) were evaluated. The effect of each massage technique on the parameters was examined, and a statistical analysis approach for evaluating massage responses is given in the conclusion.Clinical Relevance- This case study compares and contrasts the differences and advantages of each statistical approach for analyzing on studying the effects of massage and presents the response results for two massage techniques.


Tryptophane-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal.
Positive supercoils are introduced in cellular DNA in front of and negative supercoils behind tracking polymerases. Since DNA purified from cells is normally under-wound, most studies addressing the relaxation activity of topoisomerase I have utilized negatively supercoiled plasmids. The present report compares the relaxation activity of human topoisomerase I variants on plasmids containing equal numbers of superhelical twists with opposite handedness. We demonstrate that the wild-type enzyme and mutants lacking amino acids 1-206 or 191-206, or having tryptophane-205 replaced with a glycine relax positive supercoils faster than negative supercoils under both processive and distributive conditions. In contrast to wild-type topoisomerase I, which exhibited camptothecin sensitivity during relaxation of both negative and positive supercoils, the investigated N-terminally mutated variants were sensitive to camptothecin only during removal of positive supercoils. These data suggest different mechanisms of action during removal of supercoils of opposite handedness and are consistent with a recently published simulation study [Sari and Andricioaei (2005) Nucleic Acids Res., 33, 6621-6634] suggesting flexibility in distinct parts of the enzyme during clockwise or counterclockwise strand rotation.


[Indications, terms and classification of reconstructive interventions based on penetrating keratoplasty with implantation of posterior chamber intraocular lens].
Based on analysis of 750 reconstructive operations on the anterior segment of the eye, the authors classify simultaneous reconstructive interventions based on perforating keratoplasty with implantation of posterior chamber intraocular lens (IOL). Indications, terms, and technological features of such operations are defined with due consideration for the etiology of involvement of the anterior segment of the eye, corneal status, presence of the lens, and intactness of the lenticular posterior capsule. Disk posterior chamber IOLs with intracapsular fixation are preferred (in case of an intact capsule sac, with suturing to the posterior surface of the cornea) in the absence of the posterior capsule of the lens. As a result of surgery, improvement of visual acuity by 0.04-0.8 was attained in 720 patients.


[Is the semen analysis a reliable test?].
The semen analysis is one, if not the most, important and widely used clinical laboratory test to evaluate the fertility potential of the male. However, recent reports have suggested that the semen analysis is unreliable. Quality control in the andrology laboratory is often seen as problematic, and many laboratories do not routinely employ QC procedures in semen testing. Quality assurance is an often overlooked and unappreciated aspect of overall quality laboratory performance. External proficiency testing programs in andrology are not universally accepted, and the results from the few programs currently available demonstrate huge variations between laboratories. Numerous different standards and criteria are being used by andrology laboratories, making it difficult if not impossible to compare results from one laboratory to another. However, reliable semen analyses can be obtained by following several recommendations: (1) all laboratories performing the semen analysis should adopt universally accepted performance standards and criteria, (2) all laboratories performing this test should participate in external proficiency testing programs, (3) andrology laboratories should implement effective internal quality control and quality assurance programs to ensure that the results reported are accurate and reproducible, and (4) physicians should only refer their patients to, or accept semen analysis results from, laboratories that have stringently followed these recommendations.


Algebraic decomposition of fat and water in MRI.
The decomposition of magnetic resonance imaging (MRI) data to generate water and fat images has several applications in medical imaging, including fat suppression and quantification of visceral fat. We introduce a novel algorithm to overcome some of the problems associated with current analytical and iterative decomposition schemes. In contrast to traditional analytical schemes, our approach is general enough to accommodate any uniform echo-shift pattern, any number of metabolites and signal samples. In contrast to region-growing method that use a smooth field-map initialization to resolve the ambiguities with the IDEAL algorithm, we propose to use an explicit smoothness constraint on the final field-map estimate. Towards this end, we estimate the number of feasible solutions at all the voxels, prior to the evaluation of the roots. This approach enables the algorithm to evaluate all the feasible roots, thus avoiding the convergence to the wrong solution. The estimation procedure is based on a modification of the harmonic retrieval (HR) framework to account for the chemical shift dependence in the frequencies. In contrast to the standard linear HR framework, we obtain the frequency shift as the common root of a set of quadratic equations. On most of the pixels with multiple feasible solutions, the correct solution can be identified by a simple sorting of the solutions. We use a region-merging algorithm to resolve the remaining ambiguity and phase-wrapping. Experimental results indicate that the proposed algebraic scheme eliminates most of the difficulties with the current schemes, without compromising the noise performance. Moreover, the proposed algorithm is also computationally more efficient.


The role of sialic acid in the dysfibrinogenemia associated with liver disease: distribution of sialic acid on the constituent chains.
To further evaluate the role of sialic acid in the dysfibrinogenemia associated with liver disease, we studied the effect of removal of excess sialic acid residues from the fibrinogen of five patients with liver disease on the thrombin time and fibrin monomer aggregation. Patient fibrinogens containing 1.4-3.4 residues of sialic acid per molecule in excess of normal controls, with thrombin times 12-22 sec longer than normal and with abnormal fibrin monomer aggregation, were stripped of their excess sialic acid by incubation with Vibrio cholerae neuraminidase, followed by rapid removal of the enzyme by antineuraminidase antibody affinity chromatography. These partially desialylated patient fibrinogens, with a normal number of sialic acid residues remaining, exhibited normal thrombin times and normal fibrin monomer aggregation. Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of reduced normal, patient, and partially desialylated patient (sialyl-3H)-fibrinogen exhibited 60% of the radioactivity in the B beta chain and 40% in the gamma chain. There was no radioactivity detectable in the A alpha chain. These studies provide additional evidence that the increased sialic acid content of the acquired dysfibrinogenemia of liver disease is responsible for its functional defect and that the excess sialic acid is distributed on the B beta chain and gamma chains of the fibrinogen.


[Analysis of changes in heart rate and temperature of the ground squirrel Citellus undulatus in various physiological states].
Heart rate (HR) of ground squirrel C. undulatus was studied in dependence of season, level of activity, physiological state and air temperature (T). In summer HR varies from 110-130 beat/min in sleep up to 420 beat/min at flight from danger. During winter hibernation HP was minimal (3-5 beat/min) at T 1-4 degrees C, the increase in T induced the growth of HP in correspondence to the Arrenius van't Hoff law. The temperature of the body in hibernation exceeded T on 1.5-3 degrees C. The time of getting off the hibernation increased with the decrease in T (6-7 hours at -1 degree C and 2.5-3 hours at +18 degrees C). At phase of increased thermogenesis during arousal heart temperature exceeded rectal one on 10-12 degrees C and heart rate run up to 360-420 beat/min i.e. 2-3 time higher than in active state. The decrease in T stimulated the increase in HP up to 3.8 in winter and 5.3 beat/min/degree C in summer. The highest values of Q10 for HP were revealed at the beginning of hibernation (15-20) and at the beginning of arousal (6-7), in other periods Q10 was similar to the normal biological values (2-2.5). Thus, at the beginning of transitional periods changes of HP were determined mainly by endogenic mechanisms that inhibited myocardium at the beginning of hibernation and activated in arousal. Some mechanisms of coordination between activities of heart and other systems of organism are considered. The features of hit exchange providing the hibernation in wide range of T are discussed.


Cholinergic motor control of sea urchin tube feet: evidence for chemical transmission without synapses.
Isolated tube feet of Strongylocentrotus franciscanus contract briefly when the outer epithelium is touched. Similar twitch-like contractions can be induced by electrical stimulation of the outer surface of the tube foot. These responses appear to be chemically mediated. The following evidence indicates that the transmitter substance may be acetylcholine (ACh): ACh causes muscle contraction. This effect and that of electrical stimuli is potentiated by anticholinesterase agents and is antagonized by cholinergic blocking agents. Anaesthesia with chloralhydrate or chloretone abolishes responsiveness to mechanical or electrical stimulation but not to ACh. Desensitization with carbachol prevents responses to ACh and to mechanical or electrical stimulation. There are no neuromuscular synapses and no axons can be detected which cross the connective tissue layer which separates the muscle fibres from the subepithelial nerve plexus. The latter is known to contain conspicuous amounts of ACh; nerve terminals containing clear vesicles invest the outer surface of the connective tissue layer. All evidence indicates that chemical transmission involves diffusion of ACh (released from activated nerve terminals) across this connective tissue layer which is around 5 micron thick in fully extended tube feet but may have a thickness of 20 or even 25 micron in less extended ones. Calculations based on equations describing transmitter diffusion prove the feasibility of such a mechanism.


New Insights in Microbial Species Predicting Lung Function Decline in CF: Lessons from the MucoFong Project.
Several predictive models have been proposed to understand the microbial risk factors associated with cystic fibrosis (CF) progression. Very few have integrated fungal airways colonisation, which is increasingly recognized as a key player regarding CF progression. To assess the association between the percent predicted forced expiratory volume in 1 s (ppFEV1) change and the fungi or bacteria identified in the sputum, 299 CF patients from the "MucoFong" project were included and followed-up with over two years. The relationship between the microorganisms identified in the sputum and ppFEV1 course of patients was longitudinally analysed. An adjusted linear mixed model analysis was performed to evaluate the effect of a transient or chronic bacterial and/or fungal colonisation at inclusion on the ppFEV1 change over a two-year period. Pseudomonas aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and Candida albicans were associated with a significant ppFEV1 decrease. No significant association was found with other fungal colonisations. In addition, the ppFEV1 outcome in our model was 11.26% lower in patients presenting with a transient colonisation with non-pneumoniae Streptococcus species compared to other patients. These results confirm recently published data and provide new insights into bacterial and fungal colonisation as key factors for the assessment of lung function decline in CF patients.


Effects of peptide hydrophobicity on its incorporation in phospholipid membranes--an NMR and ellipsometry study.
Effects of peptide hydrophobicity on lipid membrane binding, incorporation, and defect formation was investigated for variants of the complement-derived antimicrobial peptide CNY21 (CNYITELRRQHARASHLGLAR), in anionic 1-palmitoyl-2-oleoylphosphatidylethanolamine (POPE)/1-palmitoyl-2-oleoylphosphatidylglycerol (POPG) and zwitterionic 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) membranes. Using a method combination of, e.g., ellipsometry, CD, and fluorescence spectroscopy, it was shown that peptide adsorption, as well as peptide-induced liposome leakage and bactericidal potency against Escherichia coli and Pseudomonas aeruginosa, was promoted by increasing the hydrophobicity of CNY21 through either substituting the two histidines (H) in CNY21 with more hydrophobic leucine (L) residues, or end-tagging with tritryptophan (WWW). Fluorescence spectroscopy revealed that both CNY21WWW and the WWW tripeptide localized to the polar headgroup region of these phospholipid membranes. Deuterium NMR experiments on macroscopically oriented membranes containing fully (palmitoyl) deuterated POPC (POPC-d(31)) demonstrated that both CNY21L and CNY21WWW induced disordering of the lipid membrane. In contrast, for cholesterol-supplemented POPC-d(31) bilayers, peptide-induced disordering was less pronounced in the case of CNY21L, indicating that the peptide is unable to partition to the interior of the lipid membrane in the presence of cholesterol. CNY21WWW, on the other hand, retained its membrane-disordering effect also for cholesterol-supplemented POPC-d(31). These findings were supported by pulsed field gradient NMR experiments where the lateral lipid diffusion was determined in the absence and presence of peptides. Overall, the results provide some mechanistic understanding to previously observed effects of peptide hydrophobization through point mutations and end-tagging, particularly so for complement-based antimicrobial peptides.


Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein.
The therapeutic expansion of Foxp3+ regulatory T cells (Tregs) shows promise for treating autoimmune and inflammatory disorders. Yet, how this treatment affects the heterogeneity and function of Tregs is not clear. Using single-cell RNA-seq analysis, we characterized 31,908 Tregs from the mice treated with a half-life extended mutant form of murine IL-2 (IL-2 mutein, IL-2M) that preferentially expanded Tregs, or mouse IgG Fc as a control. Cell clustering analysis revealed that IL-2M specifically expands multiple sub-states of Tregs with distinct expression profiles. TCR profiling with single-cell analysis uncovered Treg migration across tissues and transcriptional changes between clonally related Tregs after IL-2M treatment. Finally, we identified IL-2M-expanded Tnfrsf9+Il1rl1+ Tregs with superior suppressive function, highlighting the potential of IL-2M to expand highly suppressive Foxp3+ Tregs.


Single-unit stability using chronically implanted multielectrode arrays.
The use of chronic intracortical multielectrode arrays has become increasingly prevalent in neurophysiological experiments. However, it is not obvious whether neuronal signals obtained over multiple recording sessions come from the same or different neurons. Here, we develop a criterion to assess single-unit stability by measuring the similarity of 1) average spike waveforms and 2) interspike interval histograms (ISIHs). Neuronal activity was recorded from four Utah arrays implanted in primary motor and premotor cortices in three rhesus macaque monkeys during 10 recording sessions over a 15- to 17-day period. A unit was defined as stable through a given day if the stability criterion was satisfied on all recordings leading up to that day. We found that 57% of the original units were stable through 7 days, 43% were stable through 10 days, and 39% were stable through 15 days. Moreover, stable units were more likely to remain stable in subsequent recording sessions (i.e., 89% of the neurons that were stable through four sessions remained stable on the fifth). Using both waveform and ISIH data instead of just waveforms improved performance by reducing the number of false positives. We also demonstrate that this method can be used to track neurons across days, even during adaptation to a visuomotor rotation. Identifying a stable subset of neurons should allow the study of long-term learning effects across days and has practical implications for pooling of behavioral data across days and for increasing the effectiveness of brain-machine interfaces.


The medical assessment of bruising in suspected child maltreatment cases: A clinical perspective.
Bruises commonly occur in children and are most often the result of a minor accidental injury. However, bruises can also signal an underlying medical illness or an inflicted injury (maltreatment). Although bruising is the most common manifestation of child physical maltreatment, knowing when to be concerned about maltreatment and how to assess bruises in this context can be challenging for clinicians. Based on current literature and published recommendations, this practice point will help clinicians to distinguish between accidental and inflicted bruises, to evaluate and manage bruising in the context of suspected child maltreatment, and to evaluate for an underlying medical predisposition to bruising.


Association between kimchi intake and asthma in Korean adults: the fourth and fifth Korea National Health and Nutrition Examination Survey (2007-2011).
This study was performed to investigate the relationship between dietary factors and asthma in a representative population-based sample of 19,659 men and women, aged 19-64 years, using data from the fourth and fifth Korean National Health and Nutrition Examination Survey (KNHANES), 2007-2011. The presence of asthma was based on self-reported physician diagnosis of asthma in the Health Interview Surveys. Food intake was estimated by trained interviewers using a 24-h recall method. The prevalence of asthma in Korean adults was 2.4%. Adults with asthma consumed fewer amounts of kimchi (P=.0444) and fish (P=.0175) but had a higher cereal intake than those without asthma (P=.0056). Multiple logistic regression analysis after controlling for confounding factors showed a significant inverse relationship between kimchi consumption and the prevalence of asthma [odds ratio (95% confidence interval) for subjects consuming 1 to <2 servings (40-79.9 g), 2 to <3 servings (80-119.9 g), and ≥3 servings (≥120 g), relative to those consuming <1 serving (<40 g): 0.726 (0.534-0.987), 0.506 (0.348-0.736), and 0.678 (0.502-0.916), respectively; P for trend=0.0131]. These results warrant future studies to explore the mechanisms responsible for the association between kimchi consumption and asthma.


Electrical transport in ion beam created InAs nanospikes.
Ion beam irradiation has previously been demonstrated as a method for creating nanowire-like semiconductor nanostructures, but no previous studies have reported on the electrical properties of those structures. In this work we describe the creation and in situ transmission electron microscopy electrical characterization of nanoscale InAs spike structures on both InAs and InP substrates fabricated using a focused ion beam erosion method. Those InAs 'nanospikes' are found to possess internal structures with varying amounts of ion damaged and single crystalline material. Nanospike electrical behavior is analyzed with respect to model electronic structures and is similar to cases of barrier limited conduction in nanowires. The different electrical responses of each nanospike are found to be the result of variation in their structure, with the conductivity of InAs nanospikes formed on InAs substrates found to increase with the degree of nanospike core crystallinity. The conductivity of InAs nanospikes formed on InP substrates does not show a dependence on core crystallinity, and may be controlled by the other internal barriers to conduction inherent in that system.


Biology of Vibrio cholera. Editorial overview.
In this monographic issue, we have the pleasure to present contributions from six of the leading laboratories at the forefront of Vibrio cholerae genetics, ecology and evolution, together with a brief tribute by Diego Romero to Doctor Jaime Ferrán y Clua, a pioneering Spanish bacteriologist who developed the first vaccine against this pathogen. V. cholerae is a free-living aquatic bacterium that interacts with and infects a variety of organisms. In humans it causes cholera, the deadly diarrhoea that was responsible for millions of deaths during seven pandemics since 1817, and still thousands every year. The Boucher lab presents a study of the ecology, evolution and dispersal of pandemic V. cholerae biotypes in relation to environmental reservoirs. They show how both species-specific and lineage-specific genetic determinants play a role in the ability of V. cholerae strains to cause pandemics, having evolved gradually over centuries. One of the key aspects that makes a particularly successful pathogen is its genomic plasticity. The V. cholerae genome contains a superintegron (SI) that is involved in development and dissemination of antibiotic resistance genes among diverse bacterial species, permitting population expansion in challenging conditions. Escudero and Mazel review the SI as a true hotspot of V. cholerae's genomic diversity and low-cost memory of adaptive functions in its complex lifestyle and ecology. Another remarkable aspect of V. cholerae 's genetics is the presence of two chromosomes. Segregation and division in multi-chromosomal becteria is relatively complex, and V. cholerae remains the paradigm. Espinosa and colleagues review the cell cycle of V. cholerae , comparing and contrasting with that of E. coli . In addition to genome plasticity, V. cholerae uses a variety of attack/defence strategies to compete and thrive in different niches, through interaction with bacteriophages, bacteria and eukaryotes. The role of phages in the life cycle of V. cholerae has been increasingly recognized and investigated over the past decade. Andrew Camilli and colleagues take us through the exciting evolutionary arms race between V. cholerae and virulent bacteriophages, based both on mechanisms of phage resistance in the bacterium and a unique phage-encoded CRISPR-Cas system used to counteract this resistance. Finally, the authors discuss the impact of these predator-prey dynamics in the context of infection, and their use as a strategy to limit cholera transmission within a community. In regards to its ability to coexist with other microbes, V. cholerae can produce effectors that are either released to the extracellular media, or delivered via intimate cell-to-cell contact such as those injected via the type VI secretion system (T6SS). The Pukatzki lab reviews the versatility of the T6SS to produce different combinations of such effectors, which establishes the strains of V. cholerae that can co-exist in the environment. After killing a cell, its DNA is released and incorporated by natural competence into other living cells, thereby being a potential source of diversification for V. cholerae's T6SS effectors. Finally, I revisisit the discovery of non-canonical D-amino acids, recently identified effectors secreted by V. cholerae which have increasingly been shown to be important in enhancing the ability of the bacterium to colonize and persist in a particular niche. I focus on recent observations that suggest different D-amino acids influence distinct cellular processes in bacteria, and dis cuss their role in modulating environmental bacterial biodiversity.


[Effects of repeated courses of electrostimulation and psychophysiologic correction on visual system characteristics in patients with poor vision of different genesis].
The effect of 5 courses of transcutaneous electrostimulation and of a combination of electrostimulation and psychophysiological correction of vision on the visual functions is assessed in 47 patients (90 eyes) with poor sigh of different genesis. Courses of 8-10-days were administered twice a year for 2.5-3 years. Cluster analysis of 13 objective and subjective parameters of vision permitted singling out patients responding to treatment well and poorly (groups 1 and 2). The absolute and differential electric activities of the central retina were increased during and between the courses in the first group while in the second group the shifts in the retina were negligible. Retinal changes are believed to reflect the general processes of adjustment of its activity to the levels needed for maintaining the integral visual functions, increased during treatment.


A safety-net antibiotic prescription for otitis media: the effects of a PBRN study on patients and practitioners.
Pediatricians can decrease antibiotic use by treating acute otitis media (AOM) with a safety-net antibiotic prescription (SNAP). This study assessed whether the practitioners of the Practice-Based Research Network who participated in the study continued to use the SNAP and report a 60-day follow-up of the study patients. Charts were reviewed of study patients for 60 days following study enrollment. A survey on antibiotic use for AOM was mailed to the 17 study practitioners (SP) and 30 randomly selected community pediatricians (CP). Eight of the SP used the SNAP more than 20 times over the year following the study vs 1 of the CP. Sixty-two percent of patients never received antibiotics. The recurrence/relapse rate was greater in children younger than 2 years old compared to those older, 34% vs 10%. Practitioners who participate in a Practice-Based Research Network study are more likely to use a study intervention than others.


Results from the Quality Research in Radiation Oncology (QRRO) survey: Evaluation of dosimetric outcomes for low-dose-rate prostate brachytherapy.
We report on quality of dose delivery to target and normal tissues from low-dose-rate prostate brachytherapy using postimplantation dosimetric evaluations from a random sample of U.S. patients. Nonmetastatic prostate cancer patients treated with external beam radiotherapy or brachytherapy in 2007 were randomly sampled from radiation oncology facilities nationwide. Of 414 prostate cancer cases from 45 institutions, 86 received low-dose-rate brachytherapy. We collected the 30-day postimplantation CT images of these patients and 10 test cases from two other institutions. Scans were downloaded into a treatment planning system and prostate/rectal contours were redrawn. Dosimetric outcomes were reanalyzed and compared with calculated outcomes from treating institutions. Median prostate volume was 33.4cm(3). Reevaluated median V(100), D(90), and V(150) were 91.1% (range, 45.5-99.8%), 101.7% (range, 59.6-145.9%), and 53.9% (range, 15.7-88.4%), respectively. Low gland coverage included 27 patients (39%) with a D(90) lower than 100% of the prescription dose (PD), 12 of whom (17% of the entire group) had a D(90) lower than 80% of PD. There was no correlation between D(90) coverage and prostate volume, number of seeds, or implanted activity. The median V(100) for the rectum was 0.3cm(3) (range, 0-4.3cm(3)). No outcome differences were observed according to the institutional strata. Concordance between reported and reevaluated D(90) values (defined as within ±10%) was observed in 44 of 69 cases. Central review of postimplantation CT scans to assess the quality of prostate brachytherapy is feasible. Most patients achieved excellent dosimetric outcomes, yet 17% had less than optimal target coverage by the PD. There was concordance between submitted target-coverage parameters and central dosimetric review in 64% of implants. These findings will require further validation in a larger cohort of patients.


Age-related fiber order in the ferret's optic nerve and optic chiasm.
Although the mammalian optic tract shows a grouping of fibers by age, with newer fibers nearer the pial surface, the possible rules for fiber ordering in the mammalian optic nerve have not been well defined. In this study, preferential labeling of the older retinal fibers in the ferret, a close relative of the cat, shows that the age-related fiber order in the ferret's optic tract reflects a systematic sorting of fibers by age that occurs in the optic nerve, and that is maintained through the optic chiasm. The older retinofugal fibers, dispersed throughout the nerve near the retina, come to be limited to the perimeter of the nerve as it passes through the optic foramen, while newer fibers come to lie nearest the center of the nerve. These newest fibers approach the ventral surface of the brain nearer the optic chiasm. In the chiasm, as in the tract, the oldest fibers lie furthest from the pial surface of the brain, while newer fibers lie nearer the surface. The age-related fiber ordering in the ferret's optic nerve, with the newest fibers initially being furthest from the surface at the optic foramen, differs from age-related orderings seen in nonmammalian vertebrates, where the newest fibers are always nearest the surface. The changing patterns of fiber ordering along the ferret's optic nerve may relate to changes in the underlying glial structure of the developing nerve.


Identification of a homogeneous class of beta 2-adrenoceptors in human platelets by (-)-125I-iodopindolol binding.
The highly specific beta-adrenoceptor radioligand (-)-125I-iodopindolol (IPIN) was used to label in membranes from human platelets beta-adrenoceptors. Binding of IPIN was at 25 degrees C saturable (Bmax = 7.4 +/- 2.5 fmoles bound/mg protein, N = 10) of high affinity (KD-value = 34.8 +/- 3.3 pM, N = 10), rapid and reversible. beta-Adrenoceptor antagonists inhibited binding of IPIN with monophasic displacement curves and pseudo Hill coefficients (nH) not significantly different from 1.0. The beta 2-selective antagonist ICI 118,551 was much more potent in inhibiting IPIN binding than the beta 1-selective antagonist bisoprolol. IPIN binding was stereospecific as indicated by the 100-times greater potencies of (-)-alprenolol and (-)-isoprenaline in inhibiting binding than their (+)-isomers. beta-Adrenoceptor agonists inhibited binding with slightly shallow displacement curves and nH-values of 0.85-0.88; the order of potency was: isoprenaline greater than adrenaline greater than noradrenaline. These results demonstrate that IPIN labels (in human platelet membranes with high affinity) a homogeneous population of beta 2-adrenoceptors with low capacity.


A Bayesian approach for dealing with uncertainties in detection of coronary artery stenosis using a knowledge-based system.
A knowledge-based system that combines subjective Bayesian methods with rules specified by cardiologists to diagnose coronary artery stenosis from postexercise myocardial perfusion scintigrams is discussed. This expert system was used to determine which of the three main coronary arteries had the dominant stenosis. The system also indicated when a patient had a normal myocardial perfusion pattern (no stenosis). The system was run on a set of scans from 91 patients, and the results were compared with an existing expert system that uses the Dempster-Shafer theory of evidence for dealing with uncertainties. The system was able to determine the coronary artery with the dominant stenosis over 90% of the time when supplied with prior knowledge that all the patients have single-vessel stenosis. The system was also able to determine with good accuracy whether a patient had a stenosed coronary artery or normal myocardial perfusion when no prior information was available. The program can be used initially to screen out patients with normal scintigrams. Once the patients with normal scintigrams have been removed, the expert system can then be run on the remaining patients and utilize prior knowledge that they have stenosed coronary arteries. This improves the reliability of the diagnosis.


Severe gastric dilatation due to superior mesenteric artery syndrome in anorexia nervosa.
Forty-seven year old female, with a history of anorexia nervosa, was admitted to a medical stabilization unit (ACUTE) complaining of abdominal pain exacerbated by oral intake, associated with nausea, and relieved by emesis. Admission body mass index was 10.6. Labs were notable for hepatitis and hypoglycemia. On her progressive oral refeeding plan, she suddenly developed severe abdominal pain. Computed tomography (CT) revealed gastric dilatation and superior mesenteric artery (SMA) syndrome. SMA syndrome is a rare complication of severe malnutrition resulting from compression of the duodenum between the aorta and the SMA. It is diagnosed by an upper gastrointestinal series or an abdominal CT. Gastric dilatation, in turn, is a rare complication of SMA syndrome to be included in the differential diagnoses of abdominal pain in severely malnourished patients as it is potentially life-threatening. The patient was switched to an oral liquid diet, began weight restoring, and had resolution of symptoms.


Management of gynecological cancers in the emergency department: Impact of precariousness and prognostic factors.
The primary objective was to determine the profile of patients consulting in an emergency department and diagnosed with a pelvic cancer. Our secondary objective was to assess the potential impact on this diagnostic trajectory on survival. A single-center retrospective study including patients managed for a pelvic cancer between January 2018 and November 2020 in the center Hospitalier Intercommunal de Creteil was conducted. Patients' characteristics were compared based on their diagnostic trajectory (emergency or referred to consultation). Precariousness was assessed using Pascal's tool based on 4 characteristics: being a beneficiary of the former Couverture Maladie Universelle (CMU) or Aide Medicale d'Etat (AME), not having complementary health insurance, being job seeking for more than 6 months and being beneficiary of allowances. A patient was defined as precarious if the Pascal tool was 'TRUE', i.e., at least one positive item. The main socio-demographic and cancer associated factors were analyzed as prognostic factors. Over the inclusion period, among the 283 eligible patients, 37.3 % (87/233) had a diagnosis of cancer following an emergency department visit. There was a significant association between precariousness, rupture of gynecological follow-up, lack of participation in national screening campaigns and the risk of being diagnosed through the emergency pathway for all cancers studied (p = 0.001). There was no difference in terms of stage at diagnostic, management (according to current guidelines), prognostic and overall survival between the two groups. Patients in a situation of precariousness are more likely to be diagnosed with cancer in an emergency department. Our study underlines the importance of precariousness as a factor determining the type of diagnostic management of gynecological cancer. Efforts should be made toward improving frail patients to primary care.


Diffusion Tensor Imaging of White Matter in Children Born from Preeclamptic Gestations.
Individuals born from pregnancies complicated by preeclampsia have an elevated risk for cognitive impairment. Deviations in maternal plasma angiokines occur for prolonged intervals before clinical signs of preeclampsia. We hypothesized that fetal brain vascular and nervous tissue development become deviated during maternal progression toward preeclampsia and that such deviations would be detectable by MR imaging. In this pilot study, 10 matched (gestational and current ages) pairs (5 boys/5 girls, 7-10 years of age) from preeclampsia or control pregnancies were examined by using diffusion tensor MR imaging. An unbiased voxel-based analysis was conducted on fractional anisotropy and mean diffusivity parametric maps. Six brain ROIs were identified for subsequent analysis by tractography (middle occipital gyrus, caudate nucleus and precuneus, cerebellum, superior longitudinal fasciculus, and cingulate gyrus). Statistical differences were present between groups for fractional anisotropy in the caudate nucleus (offspring from preeclamptic gestation > controls), volume of the tract for the superior longitudinal fasciculus (offspring from preeclamptic gestation > controls) and the caudate nucleus (offspring from preeclamptic gestation > controls), and for parallel diffusivity of the cingulate gyrus (offspring from preeclamptic gestation > controls). These novel preliminary results along with previous results from the same children that identified altered cerebral vessel calibers and increased regional brain volumes justify fully powered MR imaging studies to address the impact of preeclampsia on human fetal brain development.


Bond swapping from a charge cloud allows flexible coordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region.
Wiskott-Aldrich syndrome protein (WASP) activates the actin-related protein 2/3 homolog (Arp2/3) complex and regulates actin polymerization in a physiological setting. Cell division cycle 42 (Cdc42) is a key activator of WASP, which binds Cdc42 through a Cdc42/Rac-interactive binding (CRIB)-containing region that defines a subset of Cdc42 effectors. Here, using site-directed mutagenesis and binding affinity determination and kinetic assays, we report the results of an investigation into the energetic contributions of individual WASP residues to both the Cdc42-WASP binding interface and the kinetics of complex formation. Our results support the previously proposed dock-and-coalesce binding mechanism, initiated by electrostatic steering driven by WASP's basic region and followed by a coalescence phase likely driven by the conserved CRIB motif. The WASP basic region, however, appears also to play a role in the final complex, as its mutation affected both on- and off-rates, suggesting a more comprehensive physiological role for this region centered on the C-terminal triad of positive residues. These results highlight the expanding roles of the basic region in WASP and other CRIB-containing effector proteins in regulating complex cellular processes and coordinating multiple input signals. The data presented improve our understanding of the Cdc42-WASP interface and also add to the body of information available for Cdc42-effector complex formation, therapeutic targeting of which has promise for Ras-driven cancers. Our findings suggest that combining high-affinity peptide-binding sequences with short electrostatic steering sequences could increase the efficacy of peptidomimetic candidates designed to interfere with Cdc42 signaling in cancer.


Role of livestock effluent suspended particulate in sealing effluent ponds.
Intensive livestock feed-lots have become more prevalent in recent years to help in meeting the predicted food production targets based on expected population growth. Effluent from these is stored in ponds, representing a potential concern for seepage and contamination of groundwater. Whilst previous literature suggests that effluent particulate can limit seepage adequately in combination with a clay liner, this research addresses potential concerns for sealing of ponds with low concentration fine and then evaluates this against proposed filter-cake based methodologies to describe and predict hydraulic reduction. Short soil cores were compacted to 98% of the maximum dry density and subject to ponded head percolation with unfiltered-sediment-reduced effluent, effluent filtered to <3 μm, and chemically synthesized effluent. Reduction in hydraulic conductivity was observed to be primarily due to the colloidal fraction of the effluent, with larger particulate fractions providing minimal further reduction. Pond sealing was shown to follow mathematical models of filter-cake formation, but without the formation of a physical seal on top of the soil surface. Management considerations based on the results are presented.


Prevention of 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane cross-link formation in DNA by rat liver O6-alkylguanine-DNA alkyltransferase.
Previous studies have shown that the haloethylnitrosoureas introduce the cross-link 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane into DNA. This structure is evidently formed by the following sequence of events: an initial attack of a haloethyl group on the O6 position of guanine, formation of the reactive intermediate, 1,O6-ethanoguanine, and reaction of this intermediate with deoxycytidine in the opposite DNA strand. To investigate the role of O6-alkylguanine-DNA alkyltransferase in preventing the formation of this cross-link, a DNA substrate containing O6-fluoroethylguanine has been prepared by reacting DNA with N-2-fluoroethyl-N'-cyclohexyl-N-nitrosourea. The O6-fluoroethylguanine content of this substrate decreases when it is incubated at 37 degrees C and pH 7.8 in the absence of repair factors because of the chemical instability of O6-fluoroethylguanine; however, this loss is accelerated by the addition of rat liver O6-alkylguanine-DNA alkyltransferase, indicating that this repair factor recognizes and repairs O6-fluoroethylguanine in DNA; furthermore, by using [chloroethyl-14C]N-chloroethyl-N'-cyclohexyl-N-nitrosourea, it can be shown directly that the addition of rat liver O6-alkylguanine-DNA alkyltransferase prevents 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane formation. These studies link the presence of repair activity to the prevention of a specific cytotoxic lesion in DNA.


Pseudarthrosis in primary fusions for adult idiopathic scoliosis: incidence, risk factors, and outcome analysis.
A retrospective study. To analyze the incidence, characteristics, risk factors, and Scoliosis Research Society Instrument-24 (SRS-24) outcome scores of pseudarthrosis in adult idiopathic scoliosis primary fusions. The healing of spinal fusion is complex and difficult to study in a clinical setting. There are no detailed reports on pseudarthrosis in primary fusion for adult idiopathic scoliosis since the introduction of "modern" segmental fixation techniques. A retrospective chart and radiographic review of 96 patients (average age 42.2 years; range 18.2-62.9 years) with adult idiopathic scoliosis undergoing first time (primary) spinal instrumentation and fusion with a minimum 2-year follow-up (average 5.9 years; range 2-16.8 years) treated at a single institution between 1985 and 2001 were analyzed. Sixteen patients had pseudarthroses (17%). Fifty-nine percent of the pseudarthroses occurred between T9 and L1, and 81% presented with multiple levels involved (2-6 levels). The site of crosslinks or dominoes correlated with pseudarthrosis site in 69%. Pseudarthroses were detected radiologically at 32.4 months (range 12-67 months) postoperatively. Patient age at surgery more than 55 years significantly correlated with pseudarthrosis (P = 0.007). The number of fused levels more than 12 vertebrae is also significantly correlated with pseudarthrosis (P = 0.03). Smoking history and comorbidity did not increase the pseudarthrosis rate (P = 0.71 and 0.19, respectively). A larger preoperative Cobb angle (> or =70 degrees) and a greater thoracic kyphosis (T5-T12 >40 degrees) did not correlate with a higher pseudarthrosis rate (P = 0.76 and 0.73, respectively). Thoracolumbar kyphosis (T10-L2 > or =20 degrees) correlated with a significantly higher pseudarthrosis rate (P < 0.0001). Preoperative global sagittal and coronal imbalance did not increase the pseudarthrosis rate (P = 0.45 and 0.62, respectively). Patients with pseudarthrosis had lower SRS-24 scores than those without (P = 0.01). CONCLUSION.: The incidence of pseudarthrosis following adult idiopathic scoliosis primary fusion was 17%. The pseudarthrosis was most likely to occur at the thoracolumbar junction. Older patients (>55 years), longer fusion (>12 vertebrae), and those with thoracolumbar kyphosis (> or =20 degrees) demonstrated increased risk for pseudarthrosis. Patients' outcomes as measured by the SRS-24 were "negatively" affected by the pseudarthrosis.


Estimating costs of care for meningitis infections in low- and middle-income countries.
Meningitis infections are often associated with high mortality and risk of sequelae. The costs of treatment and care for meningitis are a great burden on health care systems, particularly in resource-limited settings. The objective of this study is to review data on the costs of care for meningitis in low- and middle-income countries, as well as to show how results could be extrapolated to countries without sound data. We conducted a systematic review of the literature from six databases to identify studies examining the cost of care in low- and middle-income countries for all age groups with suspected, probable, or confirmed meningitis. We extracted data on treatment costs and sequelae by infectious agent and/or pathogen, where possible. Using multiple regression analysis, a relationship between hospital costs and associated determinants was investigated in order to predict costs in countries with missing data. This relationship was used to predict treatment costs for all 144 low- and middle-income countries. The methodology of conducting a systematic review, extrapolating, and setting up a standard database can be used as a tool to inform cost-effectiveness analyses in situations where cost of care data are poor. Both acute and long-term costs of meningitis could be extrapolated to countries without reliable data. Although only bacterial causes of meningitis can be vaccine-preventable, a better understanding of the treatment costs for meningitis is crucial for low- and middle-income countries to assess the cost-effectiveness of proposed interventions in their country. This cost information will be important as inputs in future cost-effectiveness studies, particularly for vaccines.


Characterization of the Complete Mitochondrial Genome and Identification of Signature Sequence of Indian Wild Pig.
Mitochondrial DNA (mtDNA) serves as a valuable molecular marker for constructing matrilineal genealogies and tracing the evolutionary history of animals. This study aimed to characterize the complete mitochondrial genome of the Indian wild pig (IWB) (Sus scrofa cristatus) and identify IWB-specific DNA sequences that could be used as genomic signatures to differentiate IWB from domestic Indian pigs (IDP) in forensic cases. For the purpose, three wild IWB from a rescue centre were used for the characterization of the mitochondrial genome of the IWB. The mitochondrial genome was sequenced by the primer walking technique using 30 overlapping primers. The mitochondrial genome of the IWB was found to be 16,689 bp long containing 37 genes coding for 2 rRNAs, 22 tRNAs, 13 protein coding genes, and 1 D-loop region similar to the mitogenome of other pigs. Sequence analysis of the D-loop of IWB with other IDP indicated some signature sequence for IWB like duplication and transition event from 1090-1099th position, deletion of a 10 bp sequence at the 755th position, insertion of (CA) at the 137th position, and substitution of AT to GA at the 638th position. These variations specially the duplication along with transition event causes creation of unique signature sequence (-ACACAAACCT-) in the IWB that could serve as signature sequences for the IWB and be used as markers for differentiation of IWB from IDP breeds in academic as well as forensic or vetero-legal cases. Overall, a total of 36 polymorphic positions were identified in the IWB, with 29 sites being unique to the IWB only and seven being common to the Doom and HDK75 pig breeds. None of the common polymorphic sites were identified in prevailing domestic pig populations. Phylogenetic analysis of the mitochondrial genome revealed the distinct separation of the IWB from IDP. The results of genetic distance evaluation showed that the Doom pig breed was the closest to the IWB. This study provides valuable insights into the mitogenome characterisation, signature sequence and genetic distance analysis of the IWB and establishes a foundation for future studies on the conservation of this protected species.


A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis.
Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm(3). For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands. Using the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I.